We report a skeleton key platform for surface enhanced Raman spectroscopy (SERS) based biosensor, utilizing ordered arrays of Si nanopillars (SiNPLs) with plasmonic silver nanoparticles (AgNPs). The optimized SiNPLs based SERS (SiNPLs-SERS) sensor exhibited high enhancement factor (EF) of 2.4 × 10 8 for thiophenol with sensitivity down to 10 −13 M of R6G molecules. The ordered array of SiNPLs stabilizes the distribution of AgNPs along with the light trapping properties, which resulted in high EF and excellent reproducibility. The uniformity in the arrangement of AgNPs makes a single SiNPLs-SERS substrate to work for all types of biomolecules such as positively and negatively charged proteins, hydrophobic proteins, cells and dyes, etc. The experiments conducted on differently charged proteins, amyloid beta (the protein responsible for alzheimers), E. coli cells, healthy and malaria infected RBCs provide a proof of concept for employing universal SiNPLs-SERS substrate for trace biomolecule detection. The FDTD simulations substantiate the superior performance of the sensor achieved by the tremendous increase in the hotspot distribution compared to the bare Si sensor.